Using artificial intelligence (AI) to combine data from full-body x-ray images and associated genomic data from more than 30,000 UK Biobank participants, a study by researchers at The University of Texas at Austin and New York Genome Center has helped to illuminate the genetic basis of human skeletal proportions, from shoulder width to leg length.

The findings also provide new insights into the evolution of the human skeletal form and its role in musculoskeletal disease, providing a window into our evolutionary past, and potentially allowing doctors to one day better predict patients’ risks of developing conditions such as back pain or arthritis in later life. The study also demonstrates the utility of using population-scale imaging data from biobanks to understand both disease-related and normal physical variation among humans.

“Our research is a powerful demonstration of the impact of AI in medicine, particularly when it comes to analyzing and quantifying imaging data, as well as integrating this information with health records and genetics rapidly and at large scale,” said Vagheesh Narasimhan, PhD, an assistant professor of integrative biology as well as statistics and data science, who led the multidisciplinary team of researchers, to provide the genetic map of skeletal proportions.

Narasimhan is senior author of the team’s published paper in Science, which is titled “The genetic architecture and evolution of the human skeletal form,” in which the team concluded, “Combined, our work identifies specific genetic variants that affect the skeletal form and ties a major evolutionary facet of human anatomical change to pathogenesis.”

Humans are the only large primates to have longer legs than arms, a change in the skeletal form that is critical in enabling the ability to walk on two legs. As the authors explained, “Bipedalism is enabled by specific anatomical properties of the human skeleton, including shorter arms relative to legs, a narrow body and pelvis, and the orientation of the vertebral column.” But while the skeletal form underlies bipedalism, the team continued, the genetic basis of skeletal proportions (SPs) is not well characterized. “Despite more than a century of work in genetics investigating the development of limbs and the overall body plan, a comprehensive genetic map of variation that shapes the overall skeletal form has been absent. Specifically, which genes and how their expression regulates modular development of the forelimb, hindlimb, and other long bones have not been fully characterized.”

The scientists set out to determine which genetic changes underlie anatomical differences that are clearly visible in the fossil record leading to modern humans, from Australopithecus to Neanderthals. They also wanted to find out how the skeletal proportions that allow bipedalism might affect the risk of musculoskeletal diseases such as arthritis of the knee and hip—conditions that affect billions of people in the world and are the leading causes of adult disability in the U.S. Comparative genomic and evolutionary developmental biology approaches generated insights into the genetic basis of skeletal structure in animals including reptiles and mammals, the team continued. “However, these approaches do not provide an unbiased and comprehensive map of the genetic loci that regulate SPs and overall body plan.”

To study the genetic basis of human SPs and how they are linked to evolution and musculoskeletal disease, the researchers applied deep-learning models and methods in computer vision to derive human skeletal measurements from full-body X-ray images (dual energy x-ray absorptiometry; DXA) from 31,221 individuals in the UK Biobank. Using associated genetic data for the participants, they 145 independent genetic loci associated with skeletal proportions. In their research article summary, the team stated, “All skeletal proportions (SPs) are highly heritable (~30 to 50%), and genome-wide association studies of these traits identified 145 independent loci.”

“Our work provides a road map connecting specific genes with skeletal lengths of different parts of the body, allowing developmental biologists to investigate these in a systematic way,” said co-author Tarjinder Singh, PhD, associate member at NYGC and assistant professor in the Columbia University Department of Psychiatry.

The authors discovered that although limb proportions exhibit strong genetic sharing, they are uncorrelated with body width proportions, a finding that provides insight into the constraints placed on the evolution of the skeletal form. “Genetic correlation and genomic structural equation modeling indicated that limb proportions exhibited strong genetic sharing but were genetically independent of width and torso proportions,” the investigators further stated in their research article summary.

The team also examined how skeletal proportions associate with major musculoskeletal diseases and showed that individuals with a higher ratio of hip width to height were more likely to develop osteoarthritis (OA) and pain in their hips. Similarly, people with higher ratios of femur (thigh bone) length to height were more likely to develop arthritis in their knees, knee pain and other knee problems. People with a higher ratio of torso length to height were more likely to develop back pain. “The findings presented here of the association between specific SPs, but not overall height, and joint-specific OA highlight the biomechanical role that these proportions play in shaping stresses on the joints themselves and highlight specific risk factors of clinical relevance.”

Eucharist Kun, PhD, a UT Austin biochemistry graduate student and first author on the paper, commented, “These disorders develop from biomechanical stresses on the joints over a lifetime. Skeletal proportions affect everything from our gait to how we sit, and it makes sense that they are risk factors in these disorders.”

The results of the newly reported work also have implications for our understanding of evolution. The researchers noted that several genetic segments that controlled skeletal proportions overlapped more than expected with areas of the genome called human accelerated regions. These are sections of the genome shared by great apes and many vertebrates but are significantly diverged in humans. This provides genomic rationale for the divergence in our skeletal anatomy.

One of the most enduring images of the Renaissance—Leonardo Da Vinci’s “The Vitruvian Man”—contained similar conceptions of the ratios and lengths of limbs and other elements that make up the human body. “In some ways we’re tackling the same question that Da Vinci wrestled with,” Narasimhan said. “What is the basic human form and its proportion? But we are now using modern methods and also asking how those proportions are genetically determined.”

And as the authors noted in their paper and research article summary, respectively, “Our results provide genomic evidence of selection shaping some of the most fundamental anatomical transitions that have been observed in the fossil record in human evolution—changes in the overall skeletal form that confer the distinctive ability of humans to walk upright … Our work validates the use of deep learning models on DXA images to identify specific genetic variants that affect the human skeletal form. It also ties a major evolutionary facet of human anatomical change to pathogenesis.”

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